Inflammation is defined as the response of body tissues to injury or irritation. As such, inflammation is a fundamental, stereotyped complex of cytologic and chemical reactions of affected blood vessels and adjacent tissues in response to an injury or abnormal stimulation caused by a physical, chemical or biological agent. Inflammation usually leads to the accumulation of fluid and blood cells at the site of injury, and is usually a healing process. However, inflammation sometimes causes harm, usually through a dysfunction of the normal progress of inflammation. Inflammatory diseases are those pertaining to, characterized by, causing, resulting from, or becoming affected by inflammation. Examples of inflammatory diseases or disorders include, without limitation, asthma, lung inflammation, COPD, inflammation post infection, atherosclerosis, pain, dermatitis, chronic granulomatous diseases such as tuberculosis, leprosy, sarcoidosis, and silicosis, nephritis, amyloidosis, rheumatoid arthritis, ankylosing spondylitis, chronic bronchitis, scleroderma, lupus, polymyositis, appendicitis, inflammatory bowel disease, ulcers, Sjogren's syndrome, Reiter's syndrome, psoriasis, pelvic inflammatory disease, orbital inflammatory disease, thrombotic disease, and inappropriate allergic responses to environmental stimuli such as poison ivy, pollen, insect stings and certain foods, including atopic dermatitis and contact dermatitis.
There is a need for novel anti-inflammatory agents e.g. drugs that demonstrate improved pharmacokinetics, activity, oral bioavailability, potency or effective half-lives in vivo. Such agents may also have distinct resistance profiles, fewer side effects, less complicated dosing schedules, or have increased oral activity. There is still a need in the art for novel non-steroidal anti-inflammatory drugs (NSAIDs) that do not have the adverse side effects associated with prior art compounds. There is also a need for new and improved treatments of inflammatory diseases states and disorders.
Arachidonate 5-lipoxygenase (5-lipoxygenase, 5-LO or Alox5) is a member of the lipoxygenase family of enzymes. It catalyzes the oxidation of arachidonic acid to yield 5-hydroperoxyeicosatetraenoic acid. 5-LO inhibitors have been developed, mostly unsuccessfully to date, for the treatment of asthma and for rheumatic conditions such as rheumatoid arthritis. There are, however, a few marketed drugs; Zileuton, a 5-LO iron chelating inhibitor, which is an orally active inhibitor that blocks the production of leukotrienes (LTA4, LTB4, LTD4 and LTE4). The product is now marketed in two formulations; the original immediate-release formulation and now the extended-release formulation. The immediate release tablet was withdrawn from the United States market on Feb. 12, 2008. Zileuton's most serious side effect is liver toxicity and hence is not available to patients with liver disease. Montelukast and Zafirlukast are oral leukotriene receptor antagonists (i.e. they block the action of 5-LO enzyme products) used to treat asthma and relieve symptoms of seasonal allergies. Side effects of Montelukast include gastrointestinal disturbances, hypersensitivity reactions, sleep disorders and increased bleeding tendency. Zafirlukast product warning includes notification regarding eosinophilia, vasculitic rash, worsening pulmonary symptioms and/or cardiac complications. There is also some evidence that the use of either Montelukast or Zafirlukas is associated with a higher incidence of Churg-Straus syndrome. Hence improved anti-5-LO enzyme and/or pathway compounds are required for the treatment of inflammationary disorders. Herein are disclosed compounds with anti-inflammatory activity and anti-5-LO activity.
It was an object of the present invention to identify compounds with an inhibitory effect against arachidonate 5-lipoxygenase.
It was an object of the present invention to identify compounds effective against inflammatory disease, in particular asthma, atherosclerosis, pain, COPD, inflammation post infection, arthritis, and dermatitis.